We have discovered a protein family termed RGSs that impair signal transduction through pathways that use seven transmembrane receptors and heterotrimeric G proteins. Such receptors, when activated following the binding of a ligand such as a hormone or chemokine, trigger the G alpha subunit to exchange GTP for GDP; this causes the dissociation of G alpha and G beta-gamma subunits and downstream signaling. RGS proteins bind G alpha subunits and function as GTPase activating proteins (GAPs), thereby deactivating the G alpha subunit and facilitating their re-association with G beta-gamma. We have shown that RGS proteins modulate signaling through chemokine receptors and that they can inhibit chemotaxis. RGS1 expressing B lymphocytes fail to migrate in response to the chemokine SDF-1. Conversely, RGS1 deficient B cells obtained from mice in which the RGS1 gene has been disrupted by gene targeting have an enhanced chemotaxic response to SDF-1. Also, RGS proteins can inhibit the intracellular signaling triggered by a constitutively active G-protein coupled receptor (GPCR) such as the Kaposi?s sarcoma-associated herpes virus (KSHV-GPCR). The KSHV-GPCR has been shown to activate the Gi, Gq, G12 subfamilies of heterotrimeric G- proteins. Certain RGS proteins, in particular RGS2 and RGS3, are very efficient inhibitors of Gq signaling. Their effectiveness depends on the N-terminus of the RGS protein plus the RGS domain, the region required for its GAP activity. Certain key residues in the N-terminus have been identified as important. We have also shown that certain RGS proteins can directly inhibit the activation of adenylyl cyclase, thereby providing a mechanism by which certain RGS proteins can inhibit Gs induced cAMP production. We have demonstrated that RGS14 is highly expressed in lymphocytes and its expression levels are modulated by signaling through the B-cell and T-cell antigen receptors. RGS14 is also unique in that it is an inhibitor of G13 signaling. A yeast two- hybrid screen with RGS14 has been completed and several novel genes have been identified that encode proteins that interact with RGS14. To study the role of RGS proteins in lymphocyte development and function, RGS1 and RGS14 have been transgenically overexpressed. The consequences of their transgenic expression are now being analyzed. Furthermore RGS1 gene targeting has been accomplished and RGS3 and RGS14 are in progress. To study the consequences of persistent heterotrimeric G- protein signaling in lymphocyte development and function, transgenic mice expressing GTPase deficient G12 and G15 are being created. RGS3 and RGS4 have been shown to be phosphorylated and this phosphorylation is likely important in their translocation from the cytosol to membrane. - RGS, G-protein, chemokine, chemotaxis, lymphocytes, cAMP.